The cytokine IL17 plays an important role in the development of airway inflammation, which affects almost 300 million people worldwide. Along with Th2 cytokines, Th17 responses contribute development of asthma, and specifically targeting the cytokine producing cells will provide better ways to treat or cure this disease. While much is known about Th2 cells, less is known about Th17 responses. Conventional Th17 cells, as well as newly described natural Th17 (nTh17) cells secrete IL17, and a clearer understanding of cells should provide a wider array of potential targets that can impact this disease. We have found that the absence of tyrosine kinase Itk, tractable to pharmaceutical targeting, results in reduced differentiation of conventional Th17 cells. More excitingly, we also found that Itk negatively regulates the development of nTh17 cells, however, its precise role remains unclear. A better understanding of the role that Itk plays in Th17 cytokine production will allow us to further validate its use as a target for treating airway inflammation. Our long-range goal is to provide a detailed understanding of Th17 cell development, including nTh17, and their role in the development of lung inflammation so that they can be efficiently targeted. In this R21 application we will determine the role of Itk in conventional and natural Th17 cell differentiation and cytokine production and in the development of airway inflammation. The central hypothesis is that Itk inversely regulates the development and function of natural and conventional Th17 cells contributing to the development of disease, tested in two specific aims: 1) Determine the role of Itk in the development and function of natural and conventional Th17 cells. We show that Itk positively regulates IL17A production by conventional Th17 cells, but negatively regulates the development of the newly discovered nTh17 cells. We will use our novel transgenic mice that allow inducible reduction of Itk activity over time, to probe the paradoxical role of Itk in the development of these two cell types; 2) Determine the role of Itk in cytokine production by natural and conventional Th17 cells in a mouse model of airway inflammation. Given the importance of IL17 in airway inflammation, our finding that Itk regulates the production of this cytokine is significant. Here we will use our novel transgenic mice to probe the role of Itk in the function of conventional and natural Th17 cells in murine models of IL17- induced airway inflammation. This work is highly innovative, using unique and previously unavailable reagents and approaches to test the role of a pharmaceutically tractable kinase in the function of conventional and natural Th17 cells. Our work will have immediate impact on approaches to treat airway inflammation in humans.